Electrophysiological experiments using intracellular recording techniques and extracellular pharmacologic application have been performed on mouse spinal neurons grown in tissue culture and on molluscan central neurons. The research has focussed on two related questions: how do endogenous and exogenous ligands alter neuronal excitability? We have found that endogenous amino acids, peptides, purines and pyrimidines and exogenous benzodiazepines and barbiturates can all produce transmitter-like effects on cultured neurons. Peptides and drugs can also modulate transmitter actions. Protons per se can mimic some of these actions. We have resolved some of the pharmacologic events to the most elementary level possible using fluctuation or "noise" analysis. Cultured spinal neurons clearly allow detailed study of clinically relevant neuropharmacology at the membrane level. One insight we plan to pursue is the notion that the pharmacologic actions of some drugs may be mediated through receptors for endogenous ligands.